Pharmaceutical solution formulations containing 17-AAG

a technology of pharmaceutical solution and 17-aag, which is applied in the field of pharmaceutical solution formulations, can solve the problems of reducing the sensitivity of proteasome-mediated destruction of aag, discontinuing clinical candidates, and poor water solubility of aag

Inactive Publication Date: 2005-11-17
KOSAN BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The binding of geldanamycin to Hsp90 disrupts Hsp90-client protein interactions, preventing the client proteins from folding correctly and rendering them susceptible to proteasome-mediated destruction.
However, the hepatotoxicity and poor bioavailability of geldanamycin have lead to its discontinuation as a clinical candidate.
A limitation in the preparation of pharmaceutical formulations containing geldanamycin compounds such as geldanamycin itself and 17-AAG, especially for parenteral administration, is their very poor water solubility, only about 0.1 mg / mL at neutral pH for 17-AAG.

Method used

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  • Pharmaceutical solution formulations containing 17-AAG

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0036] This example describes the preparation of a vehicle for use in formulations of this invention, consisting of 50 volume % ethanol, 20 volume % Cremophor EL, and 30 volume % propylene glycol. Dehydrated ethanol (USP, 500 mL, 394.5 g) was mixed with Cremophor EL (BASF Aktiengesellschaft, 200 mL, 210 g). After the foregoing two components were mixed to form a homogeneous liquid, propylene glycol (USP, 300 mL, 310.8 g) was added. The combination was mixed again to homogeneity and filtered through a 0.22μ filter, to provide 1 liter of vehicle.

example 2

[0037] Following the general procedure of Example 1, another 1 L-batch of vehicle was prepared, using 450 mL (355.1 g) of ethanol, 280 mL (294 g) of Cremophor EL, and 270 mL (279.5 g) of propylene glycol. This resulted in a vehicle consisting of 45 volume % ethanol, 28 volume % Cremophor EL, and 27 volume % propylene glycol.

example 3

[0038] Following the general procedure of Example 1, additional 1 L-batches of vehicle were prepared, using 500 mL (394.5 g) of ethanol and 150 to 500 mL (157.5 to 525 g) of Cremophor EL, and 0 to 350 mL propylene glycol. This resulted in vehicles consisting of 50 volume % ethanol, 15 to 50 volume % Cremophor EL, and 0 to 35 volume % propylene glycol.

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Abstract

A pharmaceutical solution formulation containing 17-AAG in an amount of up to 15 mg / mL dissolved in a vehicle comprising (i) a first component that is ethanol, in an amount of between about 40 and about 60 volume %; (ii) a second component that is a polyethoxylated castor oil, in an amount of between about 15 to about 50 volume %; and (iii) a third component that is selected from the group consisting of propylene glycol, PEG 300, PEG 400, glycerol, and combinations thereof, in an amount of between about 0 and about 35 volume %.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60 / 570,215, filed May 11, 2004, the disclosure of which is incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] This invention relates to pharmaceutical solution formulations containing 17-allylamino-17-demethoxygeldanamycin (“17-AAG”) and methods for their preparation and use. [0004] 2. Description of Related Art [0005] Geldanamycin belongs to the ansamycin family of natural products, whose members are characterized by a benzenoid nucleus (typically a benzoquinone or hydroquinone nucleus) connected at two meta positions to form a macrolactam. Besides geldanamycin, the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin. [0006] Geldanamycin and its derivatives are the most extensively studied of the ansamycins. Although geldanamycin was originally was identified as a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/20A61K31/33
CPCA61K31/33A61K31/20A61P35/00
Inventor ZHONG, ZIYANGLICARI, PETER J.
Owner KOSAN BIOSCI
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